The aim of this multidisciplinary program project renewal is to gain a better understanding of the neural circuitry of the neostriatum and of other regions where dopamine neuronal systems appear to be important, and to ascertain how transmitter synthesis, release, and postsynaptic response are regulated. Particular emphasis will be placed on the development and plasticity of transplanted central nervous or neuroendocrine tissues to the brain after lesions have been produced, either surgically, or with specific neurotoxins. Special attention will be directed to the biochemical and electrophysiological events which accompany DA pathway activation, agonist- receptor interactions, and the biochemical, electrophysiological and behavioral consequences of these interactions. The plasticity of the ventral mesencephalic dopamine systems will be investigated, with particular regard to their responses to acute and chronic neural activity, pharmacological perturbations and the ability of transplanted fetal nervous or chromaffin cell donor tissue to develop and innervate host nervous tissue in situ. These studies should have considerable relevance to our understanding of such clinical states as Parkinson's disease, tardive dyskinesia consequent to chronic neuroleptic therapy, and other conditions in which neural degeneration and the responses to degenerative processes are major components. They should also provide insights into more rational approaches to the treatment of these conditions. The central paradigm of this project is the study of lesions of the dopamine-containing neurons of the rat nigral striatal pathway by the selective neurotoxin 6-hydroxydopamine (60HDA) and the subsequent treatment of such lesioned animals by several dopamine agonists or by transplantation of cells derived from rat fetuses, human fetuses, or other sources. The Project has two major aims: 1) to identify the effects of treatment with agonists or transplants on basal ganglia function after denervation, and 2) to identify ways to improve the efficacy of such treatments. Project 1 will make the 6-hydroxydopamine lesioned animals and analyze them electrochemically and electrophysiologically. Project 2 contributes biochemical analysis, before and after drug treatment or transplantation. Project 3 analyzes transplanted animals electrophysiologically, electrochemically, and behaviorally. Project 4 focuses on grafts of chromaffin cells and examines the effects of putative trophic factors. It also examines the feasibility of transplanting cells which contain genes to synthesize such factors, generated by recombinant DNA technology. Project 5 analyzes the transplants histologically and ultrastructurally. Core A provides administrative support. Core B oversees immunocompromised animal care and provides immunological studies. Core C provides statistical support. Core D performs receptor autoradiography and organizes treatment with dopaminergic agonists.